Antiviral nucleoside analogues

Abstract

The current invention is down to (+) an (−) enantiomers, as well as racemic mixtures of nucleoside analogs, wherein the carbohydrate portion of the analog is a dioxolane moiety and the nucleobase moiety is N 6 -carbocyclic-alkylamino-substituted-2-amino-purine moiety attached via its N 9 position to the dioxolane moiety. The compounds are useful for treating viral infections such as HBV and HIV infections, alone or in combination with other therapeutic agents.

What is claimed is:  
     
       1. A cis-nucleoside of formula (I):                    
       or a pharmaceutically acceptable salt thereof, wherein, 
       n is 1 or 2  
       R a  is chosen from H, COOH, CONH 2,  OH, SH, NH 2 , NO 2 , C 1-6 , alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halogen, COR a  wherein R a  is a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl and COOR b  wherein R b  is a C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
       R 3  is H or a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alknyl;  
       X is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, or                    
        wherein each Rc is independently chosen from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alknyl or an hydroxy protecting group; and  
       wherein said nucleoside is in the form of the (−) enantiomer, (+) enantiomer and mixtures thereof, including racemic mixtures.  
     
     
       2. A nucleoside according to  claim 1  wherein said nucleoside is present in the (−) form and is at least 95% free of the (+) form. 
     
     
       3. A nucleoside according to  claim 1  wherein said nucleoside is present in the (−) form and is at least 97% free of the (+) form. 
     
     
       4. A nucleoside according to  claim 1  wherein said nucleoside is present in the (−) form and is at least 99% free of the (+) form. 
     
     
       5. A compound according to  claim 1  wherein the hydroxy protecting group is chosen from acetyl-2-thioethyl ester, pivaloyloxymethyl ester or isopropyloxycarbonyloxymethyl ester. 
     
     
       6. A compound according to  claim 1  wherein X is H. 
     
     
       7. A compound according to  claim 1  wherein n is 1. 
     
     
       8. A compound according to  claim 7  wherein R 3  is H or methyl, and R 4  is H. 
     
     
       9. A compound according to  claim 7 , wherein R 4  is H, COOH, CONH 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or COOR b , and R b  is C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl. 
     
     
       10. A compound according to  claim 7  wherein R 4  is H, COOH, or C 1-6  alkyl. 
     
     
       11. A compound according to  claim 7  wherein R 4  is methyl or ethyl. 
     
     
       12. A compound according to  claim 7  wherein R 4  is COOH. 
     
     
       13. A compound according to  claim 7  wherein R 3  and R 4  are H. 
     
     
       14. A compound according to  claim 1 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       15. A compound according to  claim 1 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclobutylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt therof. 
     
     
       16. A compound according to  claim 1 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-[1-carboxylic acid cyclopropylamino]-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       17. A compound according to  claim 1 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3)-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       18. A compound according to  claim 1 , wherein said compound is (+)-(2S,4S)-2-hydroxymethyl-4-(2′-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (−) enantiomer. 
     
     
       19. A compound according to  claim 1 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclobutylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       20. A compound according to  claim 1 , wherein said compound is (+)-(2S,4S)-2-hydroxymethyl-4-(2′-amino-6′-cyclobutylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (−) enantiomer. 
     
     
       21. A compound according to  claim 1 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-[1-carboxylicacid-cyclopropylamino]-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       22. A compound according to  claim 1 , wherein said compound is (+)-(2S,4S)-2-hydroxymethyl-4-(2′-amino-6′-[1-carboxylicacid-cyclopropylamino]-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       23. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       24. The combination of  claim 23  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       25. The combination of  claim 23  wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       26. The combination of  claim 23  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       27. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 1  to a subject in need of such treatment. 
     
     
       28. The method according to  claim 27  wherein the viral infection is an HIV infection. 
     
     
       29. The method according to  claim 28  wherein the viral infection is an HBV infection. 
     
     
       30. A pharmaceutical formulation comprising at least one compound according to  claim 1  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       31. A compound according to  claim 2 , wherein n is 1. 
     
     
       32. A compound according to  claim 6 , wherein n is 1. 
     
     
       33. A compound according to  claim 1 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       34. A combination according to  claim 23 , wherein said at least one compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       35. A combination according to  claim 23 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       36. A combination according to  claim 23 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable said thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       37. A combination according to  claim 24 , wherein said at least one compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       38. A combination according to  claim 24 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       39. A combination according to  claim 24 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt therof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       40. A combination according to  claim 25 , wherein said at least one compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       41. A combination according to  claim 25 , wherein said al least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       42. A combination according to  claim 25 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       43. A combination according to  claim 26 , wherein said at least one compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       44. A combination according to  claim 26 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       45. A combination according to  claim 26 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       46. A method according to  claim 27 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       47. A method according to  claim 27 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       48. A method according to  claim 27 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       49. A method according to  claim 28 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       50. A method according to  claim 28 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       51. A method according to  claim 28 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       52. A method according to  claim 29 , wherein said compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       53. A method according to  claim 29 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       54. A method according to  claim 29 , wherein said compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt therof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       55. A formulation according to  claim 30 , wherein said at least one compound is cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof. 
     
     
       56. A formulation according to  claim 30 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 95% free of the corresponding (+) enantiomer. 
     
     
       57. A formulation according to  claim 30 , wherein said at least one compound is (−)-(2R,4R)-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane or a pharmaceutically acceptable salt thereof, and which is at least 97% free of the corresponding (+) enantiomer. 
     
     
       58. A method according to  claim 27 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       59. A method according to  claim 28 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       60. A method according to  claim 29 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       61. A method according to  claim 46 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       62. A method according to  claim 47 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       63. A method according to  claim 48 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       64. A method according to  claim 49 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       65. A method according to  claim 50 , further comprising administering to said subject a least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       66. A method according to  claim 51 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       67. A method according to  claim 52 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       68. A method according to  claim 53 , further comprising administering to said subject a least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       69. A method according to  claim 54 , further comprising administering to said subject at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, wherein said at least one compound and said at least one further therapeutic agent are administered either sequentially or simultaneously in separate or combined formulations. 
     
     
       70. A method according to  claim 58 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       71. A method according to  claim 59 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       72. A method according to  claim 60 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       73. A method according to  claim 61 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       74. A method according to  claim 62 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       75. A method according to  claim 63 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       76. A method according to  claim 64 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       77. A method according to  claim 65 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       78. A method according to  claim 66 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       79. A method according to  claim 67 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       80. A method according to  claim 68 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       81. A method according to  claim 69 , wherein said at least one further therapeutic agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       82. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 8  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       83. The combination of  claim 8  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       84. The combination of  claim 8  wherein the non-nucleoside reverse transciptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       85. The combination of  claim 8  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       86. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 8  to a subject in need of such treatment. 
     
     
       87. The method according to  claim 8  wherein the viral infection is an HIV infection. 
     
     
       88. The method according to  claim 8  wherein the viral infection is an HBV infection. 
     
     
       89. A pharmaceutical formulation comprising at least one compound according to  claim 8  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       90. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 9  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       91. The combination of  claim 9  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       92. The combination of  claim 9  wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine delavirdine or efavirenz. 
     
     
       93. The combination of  claim 9  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       94. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 9  to a subject in need of such treatment. 
     
     
       95. The method according to  claim 9  wherein the viral infection is an HIV infection. 
     
     
       96. The method according to  claim 9  wherein the viral infection is an HBV infection. 
     
     
       97. A pharmaceutical formulation comprising at least one compound according to  claim 9  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       98. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 10  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       99. The combination of  claim 10  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       100. The combination of  claim 10  wherein the non-nucleoside reverse transciptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       101. The combination of  claim 10  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       102. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 10  to a subject in need of such treatment. 
     
     
       103. The method according to  claim 10  wherein the viral infection is an HIV infection. 
     
     
       104. The method according to  claim 10  wherein the viral infection is an HBV infection. 
     
     
       105. A pharmaceutical formulation comprising at least one compound according to  claim 10  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       106. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 11  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       107. The combination of  claim 11  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       108. The combination of  claim 11  wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       109. The combination of  claim 11  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       110. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 11  to a subject in need of such treatment. 
     
     
       111. The method according to  claim 11  wherein the viral infection is an HIV infection. 
     
     
       112. The method according to  claim 11  wherein the viral infection is an HBV infection. 
     
     
       113. A pharmaceutical formulation comprising at least one compound according to  claim 11  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       114. A combination useful for the treatment of viral infections comprising at least one compound according to  claim 12  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       115. The combination of  claim 12  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       116. The combination of  claim 12  wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       117. The combination of  claim 12  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       118. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 12  to a subject in need of such treatment. 
     
     
       119. The method according to  claim 12  wherein the viral infection is an HIV infection. 
     
     
       120. The method according to  claim 12  wherein the viral infection is an HBV infection. 
     
     
       121. A pharmaceutical formulation comprising at least one compound according to  claim 12  together with at least one pharmaceutically acceptable carrier or excipient. 
     
     
       122. A combination useful for the treatment of viral infection comprising at lest one compound according to  claim 13  or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent chosen from nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. 
     
     
       123. The combination of  claim 13  wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 
     
     
       124. The combination of  claim 13  wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 
     
     
       125. The combination of  claim 13  wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 
     
     
       126. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to  claim 13  to a subject in need of such treatment. 
     
     
       127. The method according to  claim 13  wherein the viral infection is an HIV infection. 
     
     
       128. The method according to  claim 13  wherein the viral infection is an HBV infection. 
     
     
       129. A pharmaceutical formulation comprising at least one compound according to  claim 13  together with at least one pharmaceutically acceptable carrier or excipient.